Hippocampal ripples coincide with "up-state" and spindles in retrosplenial cortex.

During NREM sleep, hippocampal sharp-wave ripple (SWR) events are thought to stabilize memory traces for long-term storage in downstream neocortical structures. Within the neocortex, a set of distributed networks organized around retrosplenial cortex (RS-network) interact preferentially with the hippocampus purportedly to consolidate those traces. Transient bouts of slow oscillations and sleep spindles in this RS-network are often observed around SWRs, suggesting that these two activities are related and that their interplay possibly contributes to memory consolidation. To investigate how SWRs interact with the RS-network and spindles, we combined cortical wide-field voltage imaging, Electrocorticography, and hippocampal LFP recordings in anesthetized and sleeping mice. Here, we show that, during SWR, "up-states" and spindles reliably co-occur in a cortical subnetwork centered around the retrosplenial cortex. Furthermore, retrosplenial transient activations and spindles predict slow gamma oscillations in CA1 during SWRs. Together, our results suggest that retrosplenial-hippocampal interaction may be a critical pathway of information exchange between the cortex and hippocampus.

Hippocampal gamma and sharp wave/ripples mediate bidirectional interactions with cortical networks during sleep.

Hippocampus-neocortex interactions during sleep are critical for memory processes: Hippocampally initiated replay contributes to memory consolidation in the neocortex and hippocampal sharp wave/ripples modulate cortical activity. Yet, the spatial and temporal patterns of this interaction are unknown. With voltage imaging, electrocorticography, and laminarly resolved hippocampal potentials, we characterized cortico-hippocampal signaling during anesthesia and nonrapid eye movement sleep. We observed neocortical activation transients, with statistics suggesting a quasi-critical regime, may be helpful for communication across remote brain areas. From activity transients, we identified, in a data-driven fashion, three functional networks. A network overlapping with the default mode network and centered on retrosplenial cortex was the most associated with hippocampal activity. Hippocampal slow gamma rhythms were strongly associated to neocortical transients, even more than ripples. In fact, neocortical activity predicted hippocampal slow gamma and followed ripples, suggesting that consolidation processes rely on bidirectional signaling between hippocampus and neocortex.

Combining Cortical Voltage Imaging and Hippocampal Electrophysiology for Investigating Global, Multi-Timescale Activity Interactions in the Brain.

A new generation of optogenetic tools for analyzing neural activity has been contributing to the elucidation of classical open questions in neuroscience. Specifically, voltage imaging technologies using enhanced genetically encoded voltage indicators have been increasingly used to observe the dynamics of large circuits at the mesoscale. Here, we describe how to combine cortical wide-field voltage imaging with hippocampal electrophysiology in awake, behaving mice. Furthermore, we highlight how this method can be useful for different possible investigations, using the characterization of hippocampal-neocortical interactions as a case study.

Bifunctional thiourea-modified polymers of intrinsic microporosity for enantioselective α-amination of 3-aryl-2-oxindoles in batch and flow conditions.

Two novel polymers of intrinsic microporosity decorated with chiral thioureas have been used as recoverable organocatalysts in enantioselective α-amination of 3-aryl-substituted oxindoles, creating a quaternary stereocenter. Both catalysts were able to promote the reaction in excellent yields and good enantioselection. Catalyst II, with a pyridyl nucleus, was used in recycling experiments maintaining the activity without additional reactivation, and in flow processes allowing the synthesis of the amination product in multigram scale.

Chiral Bifunctional Thioureas and Squaramides and Their Copolymers as Recoverable Organocatalysts. Stereoselective Synthesis of 2-Substituted 4-Amino-3-nitrobenzopyrans and 3-Functionalized 3,4-Diamino-4 H-Chromenes.

Novel styryl-substituted thioureas and squaramides were obtained in three steps from commercially available 4-hydroxy-3,5-dichloroaniline. These organocatalysts promote cascade reactions in high yields and excellent stereoselection. By using only a 5 mol % loading of catalyst, it is possible to obtain 2,3,4-trisubstituted benzopyrans by reaction of α-amido sulfones derived from salicyladehydes and nitrostyrenes or 2,3,4-trisubstituted 4 H-chromenes by reaction of the same α-amido sulfones with (phenylsulfonyl)acetonitrile in excellent diastereo- and enantioselectivities. Two polymeric thioureas and squaramides were prepared by copolymerization of the best monomeric catalysts with styrene and divinylbenzene and used for the same transformations. These polymers behave also as excellent stereoselective catalysts that can be recovered and reused for five cycles.

Supported and Unsupported Chiral Squaramides as Organocatalysts for Stereoselective Michael Additions: Synthesis of Enantiopure Chromenes and Spirochromanes.

Novel supported chiral bifunctional squaramides have been easily prepared starting from diamines derived from natural amino acids and commercially available aminoalkyl polystyrene resins. These squaramides behave as excellent stereoselective recoverable organocatalysts in different Michael additions, in neat conditions at room temperature. The reaction on 2-(2-nitrovinyl) phenol as electrophile lead, in excellent yields and enantioselectivities, to intermediates that can be easily transformed into 4H-chromenes, and spirochromanones.

Supported bifunctional thioureas as recoverable and reusable catalysts for enantioselective nitro-Michael reactions.

The catalytic activity of different supported bifunctional thioureas on sulfonylpolystyrene resins has been studied in the nitro-Michael addition of different nucleophiles to trans-ß-nitrostyrene derivatives. The activity of the catalysts depends on the length of the tether linking the chiral thiourea to the polymer. The best results were obtained with the thiourea derived from (L)-valine and 1,6-hexanediamine. The catalysts can be used in only 2 mol % loading, and reused for at least four cycles in neat conditions. The ball milling promoted additions also worked very well.

One-pot sequential organocatalytic Michael-Tishchenko-lactonization reactions. Synthesis of enantioenriched 4,5,6-trisubstituted δ-lactones.

Enantioenriched trisubstituted lactones were obtained in good yields and moderate to very good enantioselectivities in one-pot process, which implies a sequential organocatalyzed Michael addition of ketones to enals, followed by catalytic intramolecular diastereoselective Tishchenko reaction and lactonization. The final lactones were obtained as single diastereoisomers, demonstrating that the mixture of the anti and syn diastereomers epimerized to the syn hydroxy ester during the oxido-reduction step.

The Hybrid Drive: a chronic implant device combining tetrode arrays with silicon probes for layer-resolved ensemble electrophysiology in freely moving mice.

Objective. Understanding the function of brain cortices requires simultaneous investigation at multiple spatial and temporal scales and to link neural activity to an animal's behavior. A major challenge is to measure within- and across-layer information in actively behaving animals, in particular in mice that have become a major species in neuroscience due to an extensive genetic toolkit. Here we describe the Hybrid Drive, a new chronic implant for mice that combines tetrode arrays to record within-layer information with silicon probes to simultaneously measure across-layer information.Approach. The design of our device combines up to 14 tetrodes and 2 silicon probes, that can be arranged in custom arrays to generate unique areas-specific (and multi-area) layouts.Main results. We show that large numbers of neurons and layer-resolved local field potentials can be recorded from the same brain region across weeks without loss in electrophysiological signal quality. The drive's lightweight structure (≈3.5 g) leaves animal behavior largely unchanged, compared to other tetrode drives, during a variety of experimental paradigms. We demonstrate how the data collected with the Hybrid Drive allow state-of-the-art analysis in a series of experiments linking the spiking activity of CA1 pyramidal layer neurons to the oscillatory activity across hippocampal layers.Significance. Our new device fits a gap in the existing technology and increases the range and precision of questions that can be addressed about neural computations in freely behaving mice.

Enantioselective conjugate addition of nitro compounds to α,ß-unsaturated ketones: an experimental and computational study.

A series of chiral thioureas derived from easily available diamines, prepared from α-amino acids, have been tested as catalysts in the enantioselective Michael additions of nitroalkanes to α,ß-unsaturated ketones. The best results are obtained with the bifunctional catalyst prepared from L-valine. This thiourea promotes the reaction with high enantioselectivities and chemical yields for aryl/vinyl ketones, but the enantiomeric ratio for alkyl/vinyl derivatives is very modest. The addition of substituted nitromethanes led to the corresponding adducts with excellent enantioselectivity but very poor diastereoselectivity. Evidence for the isomerization of the addition products has been obtained from the reaction of chalcone with [D(3)]nitromethane, which shows that the final addition products epimerize under the reaction conditions. The epimerization explains the low diastereoselectivity observed in the formation of adducts with two adjacent tertiary stereocenters. Density functional studies of the transition structures corresponding to two alternative activation modes of the nitroalkanes and α,ß-unsaturated ketones by the bifunctional organocatalyst have been carried out at the B3LYP/3-21G* level. The computations are consistent with a reaction model involving the Michael addition of the thiourea-activated nitronate to the ketone activated by the protonated amine of the organocatalyst. The enantioselectivities predicted by the computations are consistent with the experimental values obtained for aryl- and alkyl-substituted α,ß-unsaturated ketones.

Highly diastereo- and enantioselective direct Barbas-List aldol reactions promoted by novel benzamidoethyl and benzamidopropyl prolinamides in water.

Four novel benzamido-functionalized prolinamides have been prepared and tested as organocatalysts for enantioselective aldol reaction of aldehydes and cyclic ketones in water. In particular, prolinamide derived from achiral ethylene diamine was the best catalyst leading to anti aldols in excellent diastereomeric (up to 98/2) and enantiomeric (up to 99/1) ratios, thereby showing that lateral amide functionalities might be a key issue for facilitating "in water" chemistry. These catalysts are cheaper and easier to prepare than those previously described.

Synthesis of both enantiomers of hemiesters by enantioselective methanolysis of meso cyclic anhydrides catalyzed by alpha-amino acid-derived chiral thioureas.

Both ureas and thioureas derived from L- or D-valine act as bifunctional organocatalysts able to induce the enantioselective alcoholysis of mono-, bi-, and tricyclic meso anhydrides. The desymmetrization occurs in near quantitative yields and excellent enantiomeric ratios (up to >99:<1) under low catalyst loading. Both enantiomers of the hemiesters can be directly obtained by changing the configuration of the catalyst.

Chiral Bifunctional Thioureas and Squaramides Grafted into Old Polymers of Intrinsic Microporosity for Novel Applications.

We have prepared different polymeric chiral bifunctional thioureas and squaramides by modification of the very well-known polymers of intrinsic microporosity (PIM), specifically PIM-1 and PIM-CO-1, to be used as recoverable organocatalysts. The installation of the chiral structures into the polymers has been done in two or three steps in high yields. The catalytic activity of the resulting materials has been proved in the stereoselective nitro-Michael addition and in a cascade process, which allows the synthesis of enantioenriched 4H-chromene derivatives. Squaramide II and thiourea III have been used in six cycles maintaining their activity.

Diastereo- and Enantioselective Syntheses of Trisubstituted Benzopyrans by Cascade Reactions Catalyzed by Monomeric and Polymeric Recoverable Bifunctional Thioureas and Squaramides.

4-Vinylphenyl-substituted squaramides have been tested as organocatalysts for the diastereo- and enantioselective synthesis of trisubstituted benzopyrans via an oxa-Michael intramolecular nitro-Michael cascade reaction. Both the enantio- and diastereoselection were good to moderate, depending on the nature of the chiral scaffold in the catalyst. The diastereoselection is better for the most active catalyst because the final products epimerize at C-3 along the time. Supported squaramide sq-9 prepared by copolymerization of sq-4 with styrene and divinylbenzene is also effective in promoting the cascade reaction, and it is recoverable and reusable for five cycles maintaining the activity.

Bottom-Up Synthesis of Supported Thioureas and Their Use in Enantioselective Solvent-Free Aza-Henry and Michael Additions.

Two sets of supported chiral thioureas, which differ in the length of the tether that connects the chiral appendage to the polymer structure and the effective functionalization, have been prepared by copolymerization of styrene, novel styryl thioureas derived from l-valine, and divinylbenzene. The efficiency of these polymeric thioureas has been tested in two different enantioselective transformations, namely, aza-Henry and nitro-Michael reactions, in neat reaction conditions. The obtained results show that it is possible to recycle the thiourea, and they are able to promote the reactions with good enantioselectivity at a low catalyst loading.

A novel synthesis of enantiopure octahydropyrrolo[3,4-b]pyrroles by intramolecular [3 + 2] dipolar cycloaddition on chiral perhydro-1,3-benzoxazines.

[reaction: see text] Condensation of N-substituted glycines with chiral 3-allyl-2-formyl perhydro-1,3-benzoxazines forms an azomethine ylide that cyclizes to give octahydropyrrolo[3,4-b]pyrrole derivatives. The [3 + 2] dipolar cycloadditions are stereoespecific leading to a single diastereoisomer. The chemical yields are dependent on the reaction temperature and the presence or absence of a base.

Synthesis of Enantiopure Primary Amines by Stereoselective Ring Opening of Chiral Octahydro-1,3-benzoxazines by Grignard and Organoaluminum Reagents.

Chiral 1,3-perhydrobenzoxazines 1, 2, and 9-14, prepared by condensation of 8-(benzylamino)menthol with different aldehydes, react with alkylmagnesium bromides and trimethylaluminum leading to the open amino alcohols 3a-d, 4a-d, and 15-20 in excellent chemical yields and good to excellent diastereomeric excess. The sequential elimination of the menthol appendage by heating with P(2)O(5) and the benzyl group by hydrogenolysis lead to primary amines 7a-d, 8a-d, and 27-30 in excellent chemical yields and ee. The addition of the alkyl group from the Grignard derivatives and the methyl group from the trimethylaluminum occurs from opposite sides of the heterocycle, yielding the final primary amines with the same stereochemistry.

Thermal and Lewis Acid Catalyzed Diastereoselective Intramolecular Diels-Alder Reaction on α,ß-Unsaturated Amides Derived from (-)-8-Aminomenthol.

Stereochemical aspects of the intramolecular Diels-Alder reaction on perhydro-1,3-benzoxazines derived from (-)-8-aminomenthol bearing α,ß-unsaturated amides and the dienic component attached at C-2 are described. The thermal cyclization of 2-(2'-furyl) derivatives 2, 6, and 7 exclusively afforded mixtures of exo adducts. The product selectivity was highly dependent on the solvent of the reaction. In CH2Cl2, the kinetic products 3, 8, and 9 always predominated, whereas in hexane or toluene, less polar solvents, the thermodynamic adducts 4, 10, and 11 were formed as major diastereoisomers. In cyclizations catalyzed with equimolar or 2-fold excess of Lewis acid, the kinetic stereiosomers were predominant. Some Lewis acids catalyzed the reaction, but diethylaluminum chloride was the most effective. The cyclization on the perhydro-1,3-benzoxazine 13, bearing an open dienic component, was much less stereoselective, and a mixture of two exo and two endo possible stereoisomers were formed. Elimination of the menthol appendage in two steps by reductive ring opening of the N,O-acetal moiety and oxidation-elimination yielded enantiomerically pure tetrahydroisoindoline derivatives.

Synthesis of Enantiopure syn-beta-Amino Alcohols. A Simple Case of Chelation-Controlled Additions of Diethylzinc to alpha-(Dibenzylamino) Aldehydes.

Enantiomerically pure syn-2-amino alcohols 6 are prepared by addition of diethylzinc to chiral alpha-(dibenzylamino) aldehydes 4. The addition is highly stereoselective, leading to syn-2-(dibenzylamino) alcohols 5 with excellent diastereomeric excesses (76-98%). Debenzylation of 5 by hydrogenolysis on Pearlman's catalyst yields quantitatively the amino alcohols 6.

An efficient synthesis of enantiomerically enriched trifluoromethylated 1,2-diols and 1,2-amino alcohols with quaternary stereocenters by diastereoselective addition of TMSCF3 to chiral 2-acyl-1,3-perhydrobenzoxazines.

TMSCF3 adds to chiral 2-acyl-1,3-perhydrobenzoxazines with total diastereoselectivity leading to quaternary trifluoromethyl alcohols. Further transformation of the addition products yields enantiomerically enriched trifluoromethylated 1,2-diols and 1,2-amino alcohols.